JP2022547307A - Pharmaceutical formulations of indoleamine 2,3-dioxygenase inhibitors - Google Patents

Abstract

The present application discloses (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, which is less susceptible to salt disproportionation. It relates to pharmaceutical compositions containing methanesulfonate. TIFF2022547307000013.tif200164

Description

The present application discloses (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl), which has less heterogeneous salts and provides stable solid preparations. ) cyclohexyl)propanamide methanesulfonate.

Indoleamine 2,3-dioxygenase (“IDO” or “IDO1”) is an IFN-γ target gene that plays an important role in immune regulation and expression of its immunosuppressive functions in several ways. There is a pathophysiological relationship between IDO and cancer. Disruption of immune homeostasis is closely associated with tumor growth and progression, and generation of IDO within the tumor microenvironment is thought to facilitate tumor growth and metastasis. Moreover, increased activity levels of IDO are also associated with a variety of different tumors (Brandacher, G. et al., Clin. Cancer Res., 12(4):1144-1151 (Feb. 15, 2006)). In addition to cancer, IDO has been implicated in other conditions, immunosuppression, chronic infections, and autoimmune diseases or disorders (eg, rheumatoid arthritis).

(R)-N-(4-Chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide (“Compound I”) is commonly known as “Rinrhodostat ” and disclosed as a potent IDO inhibitor (see, for example, International Publication WO2016/073770). The methanesulfonate salt of Compound I (“Compound I-MSA”) was shown to be a salt with excellent properties.

In the development of pharmaceutical formulations, the determination and combination of excipients and how they interact with the active pharmaceutical ingredient (“API”) is one of the most important aspects. Many APIs are manufactured and formulated as salts. This is due to the improved dissolution rate and bioavailability of the solid compared to the free form of API crystals. The free form of the API has basic sites and has a very low pKa (eg, pKa 4.6), which may pose risks such as long-term storage stability problems, proton migration, and/or further disproportionation.

In the development of solid oral dosage formulations containing salts of ionic drugs, some excipients are known to convert the API to its free base. Formulation design must take into account factors that affect salt disproportionation during formulation or storage, or how it affects product quality and efficacy. Therefore, there is a need for stable pharmaceutical compositions.

Pharmaceutical compositions of Compound I-MSA suitable for oral administration are described herein.

を有する(R)-N-(4-クロロフェニル)-2-((1S,4S)-4-(6-フルオロキノリン-4-イル)シクロヘキシル)プロパンアミドメタンスルホン酸塩を、治療上有効量であって組成物の5%～40%w/w量含み;
(ii)崩壊剤としてクロスポビドンを組成物の2.0%～7.0%w/w量含み;および
(iii)滑沢剤としてステアリン酸マグネシウムを組成物の0.25%～1.75%w/w量含み;
ここで(R)-N-(4-クロロフェニル)-2-((1S,4S)-4-(6-フルオロキノリン-4-イル)シクロヘキシル)プロパンアミドメタンスルホン酸塩の総ステアリン酸マグネシウム量に対する重量比は8.0～40.0であり;および
(R)-N-(4-クロロフェニル)-2-((1S,4S)-4-(6-フルオロキノリン-4-イル)シクロヘキシル)プロパンアミドメタンスルホン酸から(R)-N-(4-クロロフェニル)-2-((1S,4S)-4-(6-フルオロキノリン-4-イル)シクロヘキシル)プロパンアミドへの塩の不均化が25重量%未満である、医薬組成物を提供する。 In a first aspect, the present invention provides, suitable for oral administration,
(i) a structure that:

(R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate having a therapeutically effective amount 5% to 40% w/w amount of the composition;
(ii) crospovidone as a disintegrant in an amount of 2.0% to 7.0% w/w of the composition; and
(iii) magnesium stearate as a lubricant in an amount of 0.25% to 1.75% w/w of the composition;
where (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate relative to total magnesium stearate the weight ratio is between 8.0 and 40.0; and
(R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid to (R)-N-(4- A pharmaceutical composition is provided wherein the disproportionation of the salt to chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide is less than 25% by weight.

In certain embodiments, the pharmaceutical composition further comprises microcrystalline cellulose as a first diluent and anhydrous lactose as a second diluent, combined in an amount of 50% to 80% w/w of the composition.

In one embodiment, the pharmaceutical composition further comprises silicon dioxide as a glidant in an amount of 1.0% to 3.0% w/w of the composition.

In certain embodiments, the pharmaceutical composition is (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide containing less than 5% by weight of . In another embodiment, the pharmaceutical composition is (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid Less than 3% by weight of disproportionated salt from salt to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide include.

In certain embodiments, the pharmaceutical composition is (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate in a weight ratio of 23.0 to 40.0 with respect to the total amount of magnesium stearate.

In certain embodiments, the pharmaceutical composition is (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate in an amount of 15% to 20% w/w of the composition.

In certain embodiments, the pharmaceutical composition comprises the first diluent and the second diluent in a weight ratio of 2:1 to 1:2.

In another embodiment, the pharmaceutical composition comprises a primary diluent in an amount of 25%-40% w/w of the composition. In a further embodiment, the pharmaceutical composition comprises a secondary diluent in an amount of 25%-40% w/w of the composition.

In one embodiment, the pharmaceutical composition comprises silicon dioxide in an amount of 2.0% w/w of the composition.

In some embodiments, the pharmaceutical composition has an internal granular phase and an external granular phase. In a further embodiment, the pharmaceutical composition has the following internal and external granular phases.
(a) internal granular phase:
(i) (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate at 12% of the composition; ~18% w/w content;
(ii) crospovidone as a disintegrant in an amount of 2% to 3% w/w of the composition;
(iii) magnesium stearate as a lubricant in an amount of 0.25% to 0.75% w/w of the composition;
(b) external granular phase:
(i) crospovidone as a disintegrant in an amount of 2% to 3% w/w of the composition; and
(ii) magnesium stearate as a lubricant in an amount of 0.50% to 1.00% w/w of the composition;

In certain embodiments, the pharmaceutical composition further comprises microcrystalline cellulose as a first diluent and anhydrous lactose as a second diluent in the internal granular phase in a total amount of 75% to 80% w/w of the composition, Silicon dioxide is included as an agent in an amount of 1.5% to 2.5% w/w of the composition.

In certain embodiments, the pharmaceutical composition exhibits (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6- (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl) from fluoroquinolin-4-yl)cyclohexyl)-propanamide methanesulfonate It contains less than 10% disproportionated salts in cyclohexyl)propanamide and has a particle range distribution as defined by D90 ranging from about 7 μm to about 165 μm.

In one embodiment, the pharmaceutical composition is (R)-N-(4-chlorophenyl)-2-((1S,4S) -4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinoline) -4-yl)cyclohexyl)propanamide containing less than 3% by weight of the disproportionated salt.

In some embodiments, the pharmaceutical composition has a particle range distribution as defined by D90 of about 10 μm to about 165 μm.

In certain embodiments, the pharmaceutical composition is (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-( (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinoline-4- Contains less than 3% by weight of salts disproportionated to yl)cyclohexyl)propanamide.

In certain embodiments, the pharmaceutical composition exhibits (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinoline- (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propane from 4-yl)cyclohexyl)-propanamide methanesulfonate Contains less than 3% by weight of salts disproportionated to amides.

In certain embodiments, the pharmaceutical composition exhibits (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinoline- (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propane from 4-yl)cyclohexyl)-propanamide methanesulfonate Contains less than 3% by weight of disproportionated salts of amides.

In certain embodiments, the pharmaceutical composition exhibits (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinoline- 4-yl)cyclohexyl)propanamide from methanesulfonic acid to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide Contains less than 3% by weight of disproportionated salts and mixtures.

In some embodiments, the pharmaceutical composition comprises a composition selected from the group consisting of tablets, crushed tablets, capsules or capsule powders, mini-tablets, and beads.

In another embodiment the pharmaceutical composition further comprises citric acid.

The following detailed description, while presenting examples, is not intended to limit the invention to only the specific embodiments described, and may best be understood in conjunction with the accompanying drawings.

Figure 1 illustrates the percent free base of tablets containing croscarmellose sodium or crospovidone as disintegrants in open high density polyethylene ("HDPE") bottles at 40°C/75% relative humidity ("RH"). do.

FIG. 2 graphically depicts the percentage of free base in tablets with various ratios of drug to magnesium stearate in open high density polyethylene bottles at 40° C./75%.

FIG. 3 illustrates an embodiment of a method for making film-coated tablets of 100 mg, 50 mg, and 25 mg Compound I-MSA.

The present invention will be more readily understood upon reading the following detailed description, taken in conjunction with the figures and examples forming a part of the invention. This invention is not limited to the particular apparatus, methods, applications, conditions or parameters described and/or presented herein, and furthermore, terminology used herein is illustrative of particular embodiments. It should be understood that it is intended to describe and is not intended to limit the claimed invention. Also, singular expressions used in the specification, including the appended claims, include the plural and reference to a particular numerical value includes at least that particular value unless explicitly stated otherwise.

As used herein, the terms “include,” “have,” “include,” and their like terms require the presence of the specified components/steps and allow the presence of other components/steps, open-ended variables is intended to be a phrase, term or word of However, these statements should also be construed to describe the composition or method as "consisting of" and "consisting essentially of" the compounds listed, and this In some cases, only the specified compound may be present with any pharmaceutical carrier, other compounds being excluded.

All ranges in this disclosure are inclusive of the stated endpoints and are independently combinable (eg, a range of "100 mg to 200 mg" includes the 100 mg and 200 mg endpoints and all intermediate values). The endpoints of the ranges and any values in this disclosure are not limited to the exact ranges or values but are approximate enough to include approximations of these ranges and/or values.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by forming acid or base salts thereof.

The term "API" refers to active pharmaceutical ingredient. The API used herein is the compound I-MSA or (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide It means methanesulfonate.

(Pharmaceutically acceptable compositions and formulations)
In embodiments of the present application, the pharmaceutical composition of the invention comprises 10% to 40% w/w API based on the weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition of the invention comprises 15% to 20% w/w API, based on the weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition of the invention comprises 17%-18% w/w of API, based on the weight of the pharmaceutical composition.

A pharmaceutical composition of the present invention includes a diluent. A diluent according to the invention may, for example, comprise a primary diluent and optionally a secondary diluent. Diluents commonly known to those of skill in the art include, for example, sugar alcohols, sugars, cellulose, starch derived diluents, and combinations thereof. More specific diluents known to those skilled in the art include dextrin, sucrose, sorbitol, sodium saccharin, acesulfame potassium, xylitol, aspartame, mannitol, starch, corn starch, PVP (polyvinylpyrrolidone), low molecular weight HPC (hydroxypropylcellulose), Microcrystalline cellulose ("MCC"), low molecular weight HPMC (hydroxypropyl methylcellulose), low molecular weight carboxymethylcellulose, ethyl cellulose, calcium hydrogen phosphate, silicified microcrystalline cellulose, alginate, gelatin, polyethylene oxide, acacia, dextrin, sucrose, Aluminum magnesium silicate, and polymethacrylate. An embodiment of the diluent of the present application is lactose (eg, anhydrous lactose, fast lactose, or a combination thereof). Another embodiment is microcrystalline cellulose (eg microcrystalline cellulose PH 302). This application contemplates the use of a combination of diluents (eg, microcrystalline cellulose and lactose).

In embodiments of the invention comprising two diluents, a first diluent and a second diluent, the ratio of the first diluent to the second diluent is from 2:1 to 1:2. In some embodiments, the ratio of first diluent to second diluent is 1:1. In some embodiments, the first diluent is microcrystalline cellulose and the second diluent is lactose.

The compositions of the invention contain 50% to 80% w/w diluent, based on the weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises 75%-80% w/w diluent, based on the weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises 35%-40% w/w of the first diluent and 35%-40% w/w of the second diluent, based on the weight of the pharmaceutical composition.

A pharmaceutical composition of the invention may include a glidant. Glidants known to those skilled in the art include, but are not limited to, silicon dioxide, colloidal silicon dioxide, talc, magnesium carbonate, particulate silicon dioxide, starch and combinations thereof. The present application contemplates the use of silicon dioxide as a fluidizing agent. The compositions of the present invention contain 1.0% to 3.0% w/w glidant, based on the weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises 1.75% to 2.25% w/w glidant, based on the weight of the pharmaceutical composition.

In one embodiment of the invention, the pharmaceutical composition comprises granules. In some embodiments, the granules of the composition can have an inner granular phase and an outer granular phase. In some embodiments, the inner granular phase contains a glidant and the outer granular phase does not contain a glidant.

The pharmaceutical composition of the invention contains a disintegrant. Disintegrants known to those skilled in the art include, for example, starch-based disintegrants, cellulose-based disintegrants, povidone-based disintegrants, and the like. Specific examples of disintegrants include, but are not limited to, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, crospovidone (cross-linked polyvinylpyrrolidone ("PVP")), carboxylate Sodium methyl starch (sodium starch glycolate), cross-linked sodium carboxymethylcellulose (croscarmellose), pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, sodium alginate, calcium carboxymethylcellulose and magnesium aluminum silicate. (Vegum). The present application contemplates the use of crospovidone (cross-linked povidone) as a disintegrant.

The pharmaceutical composition of the present invention contains 2.0% to 7.0% w/w disintegrant, based on the weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition of the present invention comprises 2.5% w/w disintegrant in the inner granular phase and 2.5% w/w disintegrant in the outer granular phase, based on the weight of the pharmaceutical composition.

A pharmaceutical composition of the invention may include a lubricant. Lubricants are well known to those skilled in the art and include, for example, stearic acid, stearates and combinations thereof. Examples of stearates include calcium stearate, magnesium stearate, sodium stearyl fumarate and combinations thereof. The lubricants of the present invention may comprise one lubricant or a combination of lubricants (ie one or more). The present application contemplates the use of magnesium stearate as a lubricant.

The pharmaceutical composition of the present invention contains from about 0.25% to about 1.75% w/w lubricant. In some embodiments, the lubricant forms part of the inner granular phase and part of the outer granular phase. In one embodiment, the pharmaceutical composition of the present invention comprises 0.25% to 0.75% w/w lubricant in the internal granular phase, based on the weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition of the invention comprises 0.50% to 1.00% w/w lubricant in the external granular phase, based on the weight of the pharmaceutical composition.

A provided composition can be formulated in a single formulation. Methods for their formulation are well known to those skilled in the art. In certain embodiments, the present invention provides formulations comprising solid formulations as tablets, crushed tablets, capsules or capsule powders, mini-tablets, or beads.

The pharmaceutical composition of the invention may contain an organic acid. The present application contemplates the use of citric acid as organic acid.

(Manufacture of tablets)
Tablets may be manufactured according to methods well known to those skilled in the art such as dry granulation (e.g. roller compactor), wet granulation (e.g. fluid bed granulation and high shear granulation), and direct compression, depending on the type of excipient used. change depending on The present application relates to a method of manufacturing tablets by dry granulation (see eg FIG. 3).

For example, tablets were manufactured according to the following general steps, also illustrated in FIG.
(1) Preblending: API and pharmaceutically acceptable excipients are blended during the manufacturing process. For example, without limitation, the API and internal granule excipients (primary diluent, optionally secondary diluent, glidant, disintegrant (other than internal granule lubricant)) are first screened and placed in a blender. In addition, a first mixing was performed to obtain a first mixture. Separately, the internal granular lubricant was sieved, mixed with the first mixture, added to the blender and mixed a second time.
(2) Dry granulation: (a) Roller compactor: API and pharmaceutically acceptable excipients were passed through a roller compactor to obtain compacts. The compact was then milled to obtain granules. (b) Milling (production of milled and sieved granules): The API and pharmaceutically acceptable excipients were milled and/or sieved.
(3) External Granular Mixing: Granules containing milled and/or sieved API and internal granular excipients were mixed with external granular excipients in final mixing.
(4) Compression: The final blend was compressed into tablets using a tablet press.
(5) The tablets were optionally film-coated with a film-coating agent.

(Example)
The following examples are provided for illustrative purposes and are not intended to limit the scope of the claims appended hereto. All references cited in these examples and throughout the specification are hereby incorporated by reference for all legal purposes to be served.

The present application provides pharmaceutical compositions comprising the methanesulfonate salt of Compound I. (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinoline-4- The chemical formula of yl)cyclohexyl) _propanamide is _{C25H28ClFN2O4S} , the molecular weight is _410.92g /mol, the molecular weight of methanesulfonate is _507.02g /mol. To achieve a drug loading of 12.5% as free base, 15.43% drug substance as methanesulfonate must be added to the formulation.

(Preliminary test of tablet formulation)
In excipient compatibility studies, compound I-MSA exhibited favorable chemical stability to commonly used pharmaceutical excipients, indicating that compound I-MSA is suitable for formulation with excipients.

Example 1: Types of disintegrants Raman imaging detected the free base in tablets under stressed conditions (40°C/75% relative humidity ("RH") open bottle) and compound I-MSA. This suggested that salt disproportionation had occurred. Following this observation, several factors in the disproportionation of methanesulfonate to the free base were evaluated. The factor that surprisingly had an influence was the type of disintegrant.

Cations (eg Na ⁺ , Ca ²⁺ , or Mg ²⁺ ) have been found to accelerate and induce disproportionation of methanesulfonate. Croscarmellose sodium was the source of sodium ions suspected to be the cause of the disproportionation of methanesulfonate during the formulation development. Therefore, crospovidone was evaluated as a tablet disintegrant instead. Tables 1 and 2 show tablets containing crospovidone.

Table 1 shows the ingredients of the pharmaceutical composition, including the function of the ingredients as well as the %w/w of the composition. Pharmaceutical compositions were formulated into 100 mg, 50 mg, and 25 mg tablets as shown in the table.

Table 2 illustrates different tablet compositions (or formulations) containing crospovidone and either magnesium stearate or stearic acid as lubricants in 100 mg tablets.

Comparative compositions containing croscarmellose sodium are shown in Table 3. Compositions containing croscarmellose sodium in Table 3 were compared to compositions containing crospovidone such as in Table 1. A long-term stability test was performed on the composition, as shown in FIG. It shows the amount of free base in two tablet compositions containing croscarmellose sodium or crospovidone. Surprisingly, the amount of free base was higher in the composition containing crospovidone (45.7% when stored in the open system at 40°C/75% RH for 24 weeks) compared to the composition containing croscarmellose sodium (45.7%). 12.1%) was found to be much lower.

Table 4 summarizes the free base levels observed under different conditions for up to 6 months of storage. As shown in Table 4, the data confirmed that the addition of croscarmellose sodium to the composition facilitated salt disproportionation during storage. Therefore, crospovidone was substituted for croscarmellose sodium as the disintegrant in the final tablet composition. The results also showed that the tablet blends were less prone to salt disproportionation than the coated tablets. 5 g of the final mixture stored in HDPE bottles (200 mL) at 25° C./60% RH for 24 weeks had less than 3% conversion to the free base.

Example 2: API/Magnesium Stearate Ratio Referring to Table 5, data shows that the API/magnesium stearate ratio in the composition affects the amount of methanesulfonate disproportionated. FIG. 2 shows the percent free base content of tablet compositions (or formulations) with various drug load/magnesium stearate ratios after 4 weeks of storage in open HDPE bottles at 40° C./75% RH. Compositions containing croscarmellose sodium or crospovidone as a disintegrant decreased the amount of free base as the drug load/magnesium stearate ratio increased (see Table 5). However, it was also observed that too high a drug load/magnesium stearate ratio increased processing parameters such as powder flowability and stickiness during roller compactor or tableting. Therefore, although a higher drug load/magnesium stearate ratio was associated with higher stability, a minimum amount of magnesium stearate was essential.

Example 4: Lubricant Evaluation In Table 6, compositions containing both magnesium stearate and stearic acid were evaluated for their effect on salt disproportionation. Comparing the compositions in Table 6 under open system conditions of 40°C/75% RH for 4 weeks, salt disproportionation was reduced when stearic acid was used as a lubricant (the free base content was less than stearic acid <3% for stearic acid compared to ~9% for magnesium). However, it has been found that higher amounts of stearic acid require as much lubricant as magnesium stearate. When the composition containing magnesium stearate was protected from humidity and elevated temperatures, the composition had similar levels of salt disproportionation as the stearic acid composition.

Example 5 Effect of Surface Area on Stability Two selected coated tablets were subjected to stress loading conditions to examine the differences between blends and compacts. The data in Table 7 (see also Table 4) show that the final blend is less prone to salt disproportionation, and mechanical stress during compression accelerates the amount of free base detected in the tablet. It was suggested that the

Data for both free base percentages are summarized in Table 7.

Example 6 Effect of Particle Size on Stability In a study of the effect of compound I-MSA on particle size stability, the particle size to surface area ratio of compound I-MSA did not affect stability at all. After 12 weeks in open system conditions of 40°C/75% RH, Applicants have tested an inventive composition containing unmilled API (larger particles with a D90 of 165 µm showed a free base content of about 9.4%) and milled. The amount of free base was measured in compositions containing API (small particles with a D90 of <20 μm showed a free base amount of about 10.4%). The results show a comparison of salt disproportionation amounts.

Those skilled in the art recognize that microparticles (drugs with small particle size) are more susceptible to atmospheric oxygen, temperature, light, humidity, and interacting excipients, relative to larger or coarser particle sizes. evaluated as unstable. In other words, it is known that a pharmaceutically active ingredient with a small particle size is more likely to cause disproportionation than one with a large particle size. In the present application, it was shown that particle size has no effect in the range of about 7 μm to 165 μm. This result was surprising since the ratio of particle size to surface area is known to affect stability with higher surface areas.

表8に示されるように、乾燥剤を入れた高密度ポリエチレン(HDPE)ボトルに入れた錠剤、alu/alu(アルミニウム-アルミニウムホイルブリスター)に密封された錠剤は、25℃/60%相対湿度(RH)、30℃/75%相対湿度、および40℃/75%相対湿度の条件で6ヶ月間保管しても、塩の不均化量は検出極限値未満であった。ポリ塩化ビニル/ポリクロロトリフルオロエチレン(PVC/ACLAR(登録商標))ブリスターで6ヶ月経過後の遊離塩基量は、4.2%であった。 Example 7: Differences in stability between packages

As shown in Table 8, tablets contained in desiccant-filled high-density polyethylene (HDPE) bottles, tablets sealed in alu/alu (aluminum-aluminum foil blisters) were stored at 25°C/60% relative humidity ( RH), 30°C/75% relative humidity, and 40°C/75% relative humidity for 6 months, the amount of salt disproportionation was below the limit of detection. The free base level after 6 months in polyvinyl chloride/polychlorotrifluoroethylene (PVC/ACLAR®) blisters was 4.2%.

The examples and embodiments described herein are set forth for illustrative purposes only, and various adaptations or modifications in some of the embodiments are within the scope of the invention and the appended claims.

Claims (23)

(i) a structure that:

(R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate having a therapeutically effective amount comprising from 5% to 40% w/w amount of the composition;
(ii) crospovidone as a disintegrant in an amount of 2.0% to 7.0% w/w of the composition; and
(iii) magnesium stearate as a lubricant in an amount of 0.25% to 1.75% w/w of the composition;
where the weight of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate relative to total magnesium stearate the ratio is between 8.0 and 40.0; and
(R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid to (R)-N-(4- A pharmaceutical composition suitable for oral administration having less than 25% by weight disproportionation of the salt to chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide thing. 2. The pharmaceutical composition of claim 1, further comprising microcrystalline cellulose as a first diluent and anhydrous lactose as a second diluent, combined in an amount of 50% to 80% w/w of the composition. 2. The pharmaceutical composition of Claim 1, further comprising silicon dioxide as a glidant in an amount of 1.0% to 3.0% w/w of the composition. (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid to (R)-N-(4- 2. The pharmaceutical composition of claim 1, wherein the disproportionation of the salt to chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide is less than 5% by weight. . (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid to (R)-N-(4- 2. The pharmaceutical composition of claim 1, wherein the disproportionation of the salt to chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide is less than 3% by weight. . The weight ratio of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate to total magnesium stearate is 2. The pharmaceutical composition of claim 1, which is between 23.0 and 40.0. (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate from 15% to 20% of the composition 2. The pharmaceutical composition of claim 1, comprising a w/w amount. 3. The pharmaceutical composition of claim 2, comprising the first diluent and the second diluent in a weight ratio of 2:1 to 1:2. 3. The pharmaceutical composition of claim 2, comprising the first diluent in an amount of 25% to 40% w/w of the composition. 3. The pharmaceutical composition of Claim 2, comprising the secondary diluent in an amount of 25% to 40% w/w of the composition. 4. The pharmaceutical composition of claim 3, comprising silicon dioxide in an amount of 2.0% w/w of the composition. 2. The pharmaceutical composition of Claim 1, wherein the composition has an internal granular phase and an external granular phase. (a): (i) Composition of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate (ii) crospovidone as a disintegrant in an amount of 2% to 3% w/w of the composition; (iii) magnesium stearate as a lubricant in the composition. Inner granular phase and
(b): (i) crospovidone as a disintegrant in an amount of 2% to 3% w/w of the composition; (ii) magnesium stearate as a lubricant in an amount of 0.50% to 1.00% w/w of the composition. having an external granular phase,
13. The pharmaceutical composition of claim 12. The internal granular phase further comprises microcrystalline cellulose as a first diluent and anhydrous lactose as a second diluent in a total amount of 75% to 80% w/w of the composition, and silicon dioxide as a glidant of 1.5 of the composition. 14. The pharmaceutical composition of claim 13, comprising an amount of % to 2.5% w/w. (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propane after 12 weeks at 40°C and 75% relative humidity 10 disproportionated salts from amidomethanesulfonic acid to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide 2. The pharmaceutical composition of claim 1, which is less than % by weight and has a particle size distribution as defined by D90 ranging from about 7 μm to about 165 μm. (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinoline) after storage for 24 weeks at 25°C and 60% relative humidity in a high-density polyethylene bottle (200 cc) -4-yl)cyclohexyl)propanamide from methanesulfonic acid to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide 2. The pharmaceutical composition of claim 1, wherein the disproportionated salt is less than 3% by weight. 2. The pharmaceutical composition of claim 1, wherein the particle size distribution as defined by D90 ranges from about 10 μm to about 165 μm. (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl after 6 months at 25°C and 60% relative humidity in a blister pack ) propanamide methanesulfonic acid disproportionated salt to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide 2. The pharmaceutical composition of claim 1, wherein the is less than 3% by weight. (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamidemethane after 4 weeks at 25°C and 60% relative humidity 3% by weight of disproportionated salt of sulfonic acid to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide 2. The pharmaceutical composition of claim 1, which is less than (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamidemethane after 4 weeks at 40°C and 75% relative humidity 3% by weight of disproportionated salt of sulfonic acid to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide 2. The pharmaceutical composition of claim 1, which is less than (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinoline) after 24 weeks in a closed system at 25°C and 60% relative humidity when the composition is a mixture -4-yl)cyclohexyl)propanamide from methanesulfonic acid to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide 2. The pharmaceutical composition of claim 1, wherein the disproportionated salt is less than 3% by weight. 2. The pharmaceutical composition of claim 1, wherein the composition is selected from the group consisting of tablets, crushed tablets, capsules or capsule powders, mini-tablets, and beads. 2. The pharmaceutical composition of claim 1, further comprising citric acid.

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